Genetic Analysis of Cortical Development in Mice

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DESCRIPTION (provided by applicant): An early step in the creation of the nervous system is the generation of neurons and glial cells, the building blocks of all neural circuits. During development, some cells exit the cell cycle and differentiate into neurons or glia, while others reenter the cell cycle and remain as progenitors. Both extrinsic factors (such as peptide growth factors) and intrinsic factors (such as cell-surface receptors) play important roles in the regulation of proliferation, fate specification, and differentiation. The goal of the present proposal is to test the roles of these molecules in neurogenesis and patterning of the developing cerebral cortex. Such studies have been hampered by the realization that relatively small numbers of gene families are utilized over and over during development, with the outcome of a signaling event determined largely by the type of the responding cell and the developmental context in which a signal is presented. Because of the repeated utilization of a small set of signals at a number of different times, places, and stages of development, it can be difficult to use genetics explore the role of a particular signaling system in a particular tissue in vivo. We will use conditional molecular genetic techniques in the mouse to explore the role of extrinsic signaling molecules and their receptors in the production of cortical neurons in vivo, and to compare directly the roles of these signaling systems at distinct times during development. By using mice that express the bacteriophage recombinase Cre in telencephalic progenitor cells, we will generate conditional knockouts or express dominant negative forms of signaling molecules in the developing brain. We will focus on the roles of Bone Morphogenetic Proteins (BMPs) and Fibroblast Growth Factors (FGFs), in the control of patterning, cell number, phenotype, and differentiation in the developing cerebral cortex, Our first aim addresses the hypothesis that BMP signaling induces the development of the dorsal midline. We will perform conditional knockouts of Bmp4 or its major receptor Bmpr1a, either alone or in combination with a null mutation in Bmpr1b, at the earliest stages of telencephalic specification and analyze the effects of each mutation on cerebral patterning and dorsal midline development. The second aim is to examine the role of FGF signaling in the development of anterior-posterior patterning and the formation of cortical areas. We will generate conditional knockouts of the FGF receptors Fgfr1 and Fgfr2, alone or in combination with a null mutation in Fgfr3, to assess the roles of these signaling molecules in patterning cortical areas, Our third aim uses genetics to explore the opposing roles of BMP and FGF signaling in cortical cell proliferation (stimulated by FGFs), neurogenesis (promoted by BMPS), and the production of glia.